A new report in Nature Communications has identified a key role for the RNA-binding protein Staufen1 (STAU1) in the pathogenesis of spinocerebellar ataxia type 2 (SCA2), a form of cerebellar ataxia caused by CAG repeat expansions in the ataxin 2 gene (ATXN2). STAU1 was found to contribute to dysregulation of RNA metabolism through an interaction with the ATXN2 protein.
“Since we identified the ATXN2 gene in 1996, we have worked to understand its function in neurodegeneration,” explains study leader Stefan Pulst. “STAU1 was known to be involved in RNA transport and degradation, as well as in translational control, but a role in neurodegeneration had not been recognized.”
Pathologically, SCA2 is characterized by accumulation of ATXN2 in stress granules, which are aggregates of RNA and protein that form under conditions of cellular stress and consist largely of stalled mRNA translation initiation complexes. Pulst and colleagues observed colocalization of STAU1 and ATXN2 in stress granules in fibroblasts from patients with SCA2 and in cerebellar Purkinje cells in an SCA2 mouse model.
The researchers also showed that STAU1 levels were elevated in cell lines from patients with SCA2 and in cerebellar extracts from SCA mice. This STAU1 overexpression was associated with aberrant processing of a variety of mRNAs, including PCP2, which is expressed in Purkinje cells and is depleted in SCA2. Reduction of STAU1 levels by RNA interference restored PCP2 expression in cell lines. In addition, Stau1 haploinsufficiency alleviated the pathological and behavioural phenotypes of SCA2 mice.
Pulst and colleagues observed colocalization of STAU1 and ATXN2 in stress granules
“We are working on understanding the precise mechanisms by which increased STAU1 abundance is detrimental to neurons,” says Pulst. “We are also identifying antisense oligonucleotides to target STAU1 with the goal of testing these compounds in animal models of human neurodegenerative diseases, including amyotrophic lateral sclerosis.”
References
Original article
Paul, S. et al. Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration. Nat. Commun. 9, 3648 (2018)
Further reading
Ashizawa, T. et al. Spinocerebellar ataxias: prospects and challenges for therapy development. Nat. Rev. Neurol. https://doi.org/10.1038/s41582-018-0051-6 (2018)
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Wood, H. Stressing a role for Staufen1 in SCA2 pathogenesis. Nat Rev Neurol 14, 634 (2018). https://doi.org/10.1038/s41582-018-0080-1
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DOI: https://doi.org/10.1038/s41582-018-0080-1
